Ann West
Joseph Brandt Professor, Chemistry and Biochemistry Office location: CHBA 220; Lab location: PHSC 219E Office phone: 405-325-1529; Lab phone: 405-325-1532 awest at ou dot edu http://chem.ou.edu/~ahw/groupweb/index.html Ph.D., Genetics - Yale University, 1991Research:
In prokaryotic organisms, adaptive responses to environmental changes such as nutrient limitation, oxygen deprivation, and osmotic shock are regulated by so-called two-component signal transduction pathways. These systems have in common a biochemical strategy involving phosphoryl transfer between two protein components: a histidine protein kinase and a response regulator protein. The histidine kinase is typically a transmembrane receptor that upon ligand stimulation undergoes autophosphorylation of a specific histidine residue within the cytoplasmic signaling domain. The phosphoryl group is then transferred to a specific aspartic acid residue on the response regulator protein. Phosphorylation of the response regulator results in the activation of either an associated or downstream effector function. For several decades, two-component signal transduction pathways were thought to be restricted to the bacterial kingdom. However, it is now recognized that eukaryotic organisms, such as plants and fungi, have proteins that are homologous to the bacterial histidine kinases and response regulators. With higher complexity than typical two-component signaling pathways, osmoregulation in the yeast, Saccharomyces cerevisiae, is mediated by a multi-step phosphorelay mechanism involving three proteins, the SLN1 sensor histidine kinase, the phosphorelay protein YPD1, and the response regulator SSK1. SSK1 serves to activate a downstream mitogen-activated protein (MAP) kinase cascade. The West Group is interested in elucidating the role of phosphorylation and dephosphorylation in regulating protein function within the yeast phosphorelay signaling pathway. Experiments are directed at biochemical characterization of the phosphoryl transfer reactions mediated by SLN1, YPD1, and SSK1, and elucidation of protein structures by X-ray crystallography. Since these pathway components are not found in humans, they represent novel targets for potential antifungal drug development.
Selected Publications:
Zhao, X., Copeland, D.M., Soares, A.S. & West, A.H. (2008) Crystal structure of a complex between the phosphorelay protein YPD1 and the response regulator domain of SLN1 bound to a phosphoryl analog. J. Mol. Biol., 375: 1141-1151.
Tan, H., Janiak-Spens, F. & West, A.H. (2007) Functional characterization of the phosphorelay protein Mpr1p from Schizosaccharomyces pombe. FEMS Yeast Res., 7: 912-921.
Menon, V., Li, D., Chauhan, N., Rajnarayanan, R., Dubrovska, A., West, A.H. & Calderone, R. (2006) Functional studies of the Ssk1p response regulator protein of Candida albicans as determined by phenotypic analysis of receiver domain point mutants. Mol. Microbiol., 62: 997-1013.
Janiak-Spens, Cook, P.F. & West, A.H. (2005) Kinetic analysis of YPD1-dependent phosphotransfer reactions in the yeast osmoregulatory phosphorelay system. Biochemistry, 44: 377-386.
Porter, S.W. & West, A.H. (2005) A common docking site for response regulators on the yeast phosphorelay protein YPD1. Biochim. Biophys. Acta, 1748: 138-145.
Xu, Q., Porter, S.W. & West, A.H. (2003) The yeast YPD1/SLN1 complex: Insights into molecular recognition in two-component signaling systems. Structure, 11: 1569-1581.
Porter, S.W., Xu, Q. & West, A.H. (2003) Ssk1p response regulator binding surface on histidine-containing phosphotransfer protein Ypd1p. Euk. Cell, 2: 27-33